Signalling cascades generated from fibroblast growth factor receptors (FGFRs) have been established as key factors in the control of cell proliferation, migration, and differentiation for many types of cells (Fernig D and J T Gallagher. (1995). Fibroblast growth factors and their receptors: An information network controlling tissue growth morphogenesis and repair. Prog Growth Factor Res 5:353-377; Boilly B, A S Vercoutter-Edouart, H Hondermarck, V Nurcombe and X Le Bourhis. (2000). FGF signals for cell proliferation and migration through different pathways. Cytokine Growth Factor Rev 11:295-302; Marie P J. (2003). Fibroblast growth factor signalling controlling osteoblast differentiation. Gene 316:23-32. Eswarakumar V P, I Lax and J Schlessinger. (2005). Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139-149.).
Alternative splicing in the third immunoglobulin (Ig) loop of FGFR 1-3 transcripts result in a variety of isoforms, leading to differences in ligand binding specificity (Dell K R and L T Williams. (1992). A novel form of fibroblast growth factor receptor 2. Alternative splicing of the third immunoglobulin-like domain confers ligand binding specificity. J Biol Chem 267:21225-21229. Givol D and A Yayon. (1992). Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J 6:3362-3369.0), with the “b” and “c” isoforms generally expressed in epithelial and mesenchymal tissues, respectively Orr-Urtreger A, M T Bedford, T Burakova, E Arman, Y Zimmer, A Yayon, D Givol and P Lonai. (1993); Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev Biol 158: 475-486; Ornitz D M, J Xu, J S Colvin, D G McEwen, C A MacArthur, F Coulier, G Gao and M Goldfarb. (1996). Receptor specificity of the fibroblast growth factor family. J Biol Chem 271:15292-15297.).
Targeted disruptions of FGFRs have been shown to cause a variety of phenotypic abnormalities in mice, including embryonic lethality due to defective cell migration (FGFR1) (Partanen J, L Schwartz and J Rossant. (1998). Opposite phenotypes of hypomorphic and Y766 phosphorylation site mutations reveal a function for Fgfr1 in anteroposterior patterning of mouse embryos. Genes Dev 12:2332-2344.), impairment of bone and limb development (FGFR2) (Xu X, M Weinstein, C Li, M Naski, R I Cohen, D M Ornitz, P Leder and C Deng. (1998). Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125:753-765; Eswarakumar V P, E Monsonego-Ornan, M Pines, I Antonopoulou, G M Morriss-Kay and P Lonai. (2002). The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development 129:3783-3793.), and bone overgrowth (FGFR3) (Deng C, A Wynshaw-Boris, F Zhou, A Kuo and P Leder. (1996). Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84:911-921.). In humans, genetic studies have linked bone growth and patterning disorders, including Pfeiffer syndrome (FGFR1) (Muenke M, U Schell, A Hehr, N H Robin, H W Losken, A Schinzel, L J Pulleyn, P Rutland, W Reardon and S Malcolm. (1994). A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature Genet 8:269-274.), Crouzon syndrome (FGFR2) (Reardon W, R M Winter, P Rutland, L J Pulleyn, B M Jones and S Malcolm. (1994). Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nature Genet 8:98-103.), and achondroplasia (FGFR3) (Rousseau F, J Bonaventure, L Legeai-Mallet, A Pelet, J M Rozet, P Maroteaux, M Le Merrer and A Munnich. (1994). Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252-254.) to chromosomal mutations.
FGFR1 expression has been noted in a number of tumors (e.g. see Table 5 of WO 2005/066211).